Genetic Dissection of a VIP Link between Immune Dysfunction and Neurodevelopmental Disorders Characterized by Social Deficits

免疫功能障碍与以社交缺陷为特征的神经发育障碍之间 VIP 联系的基因剖析

• 批准号: 10569057
• 负责人: Xiaohong Lu
• 金额: $ 22.05万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569057
• 关键词: Affect; Animal Model; Bacterial Artificial Chromosomes; Behavior; Behavioral; Birth; Blood; Brain; CREB1 gene; Cells; Centers of Research Excellence; Cognitive; Cognitive deficits; Copy Number Polymorphism; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Disease; Dissection; Enterobacteria phage P1 Cre recombinase; Equilibrium; Etiology; Flow Cytometry; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Transfer Techniques; Genes; Genetic; Genetic Predisposition to Disease; Health; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunology; Impairment; Interferon Type II; Ligands; Link; Literature; Luciferases; Lymphocyte; Mediating; Meningeal; Microglia; Modeling; Molecular; Mus; Neonatal; Neurodevelopmental Disorder; Pathogenicity; Pathologic Processes; Patients; Pattern; Population; Reporter; Reporting; Research; Resolution; Risk Factors; Role; Schizophrenia; Series; Shapes; Signal Transduction; Social Behavior; Social Interaction; Symptoms; T-Lymphocyte; Th2 Cells; Time; Transgenes; Transgenic Mice; Translating; Vasoactive Intestinal Peptide; Work; antagonist; autism spectrum disorder; autistic children; cell type; cytokine; design; designer receptors exclusively activated by designer drugs; genetic approach; genome wide association study; genome-wide; human model; individualized medicine; innovation; insight; mouse model; neural circuit; neurodevelopment; overexpression; pathogen; postnatal; remote control; response; small molecule; social; social deficits; success; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; vasoactive intestinal peptide 2 receptor

Project 1 Project Summary/Abstract Immune dysfunction has been extensively reported in the literature as a risk factor contributing to neurodevelopmental disorders characterized by social deficits, e.g., autism spectrum disorder (ASD) and schizophrenia. From an evolutionary perspective, for many millions of years, human behavior, especially sociality, has been shaped by two ancient battling forces: pathogens and the immune system. Sickness behavior or avoidance of social interaction in ASD could thus be viewed as an immune input into the brain to evade the spreading of the pathogens. Emerging research within the last decade starts to reveal that immune inputs (e.g., meningeal immunity) can indeed affect neural circuits. The critical questions remain unanswered include whether, when and how a dysfunctional immunity can cause neurodevelopmental disorders characterized by social deficits? Besides, whether the immune system can be therapeutically targeted to ameliorate social symptoms in autism and schizophrenia? Recently, several large-scale genome-wide association studies (GWAS) pinpointed a Copy Number Variation (CNV) at the chromosomal locus 7q36.6 that is highly represented in schizophrenia and autism, with all of the microduplications (triplications) occurring within a single gene: vasoactive intestinal peptide receptor 2 (VIPR2). Importantly, VIPR2 ligand, vasoactive intestinal peptide (VIP) has been found almost tripled the normal level in the neonatal blood of children with autism. It has been well established that VIP/VIPR2 signaling modulates immunity and shifts the Th1/Th2 balance in favor of Th2 cells. All these genetic findings pinpoint a long-sought link between the social deficits and dysfunctional immunity consistently observed in neurodevelopmental disorders. To translate such a genetic vulnerability into a mechanistic and pathophysiologic insight, we have developed a series of conditional VIPR2 Bacterial Artificial Chromosome (BAC) transgenic mouse models of VIPR2 CNV. The conditional design of the BAC allows switching-off the transgene in desired spatial-temporal patterns, controlled by Cre recombinase, thus facilitating dissection of the inflicted cell populations. Genetically over-activated VIPR2 signaling elicits early postnatal microglial pruning deficits and manifests robust social deficits. Therefore, we propose the central hypothesis that over-activated VIP/VIPR2 signaling in T cells elicits abnormal immune transformation to disrupt social brain development and/or social behavior. The hypothesis will be examined in the following specific aims: Aim 1 will examine the potential pathogenic role of VIPR2 CNV in T cells to elicit systemic immune imbalance to disrupt early postnatal brain development. This aim represents the first to employ a chemogenetic approach with Designer Receptors Exclusively Activated by Designer Drugs (DREADD) together with CREB-luciferase reporter transgenesis to remotely control T cell-type-specific Gαs GPCR/PKA signaling to determine whether VIPR2 driven Th2 preferential differentiation is sufficient to elicit social deficits and brain developmental deficits. Our proposed genetic interrogation in an etiology-relevant animal model will shift the paradigm of the field by providing for the first time unequivocal causal evidence to that a dysfunctional immunity is sufficient and necessary to disrupt brain development and/or to manifest social behavioral deficits. Given that there is no disease-modifying therapy for autism and schizophrenia, our results will have an important positive impact because they lay the groundwork to the idea of tailoring of treatments (e.g., small molecule VIPR2 antagonist) targeting T cell immunity for resolution of social symptoms, which is highly innovative, and with tremendous translational value.

项目1项目摘要/摘要 免疫功能障碍已在文献中广泛报道，这是导致的危险因素 以社会缺陷为特征的神经发育障碍，例如自闭症谱系障碍（ASD）和 精神分裂症。从进化的角度来看，已有数百万年的人类行为，尤其是 社会性是由两种古老的战斗力来塑造的：病原体和免疫系统。疾病行为 因此，可以将ASD中的社会互动避免被视为对大脑的免疫输入，以逃避 病原体的传播。在过去十年中，新兴的研究开始表明免疫输入（例如， 脑膜免疫确实会影响神经回路。关键问题仍未得到答复 功能失调的免疫何时以及如何引起以社会为特征的神经发育障碍 缺陷？此外，是否可以将免疫系统用于改善社会症状 自闭症和精神分裂症？最近，几项大规模基因组关联研究（GWAS）精确了 染色体基因座7q36.6的拷贝数变化（CNV）在精神分裂症中高度代表 和自闭症，所有微型复制（一式三份）发生在单个基因中：血管活性肠 肽受体2（VIPR2）。重要的是，已经发现VIPR2配体，血管活性肠肽（VIP）几乎被发现 自闭症儿童的新生儿血液中正常水平的两倍。 VIP/VIPR2已经很好地确定 信号调制的免疫力并转移TH1/TH2平衡，有利于Th2细胞。所有这些遗传发现 查明社会缺陷与功能失调的免疫力之间的长期联系 神经发育障碍。将这种遗传脆弱性转化为机械和病理生理 洞察力，我们已经开发了一系列条件VIPR2细菌人造染色体（BAC）转基因 VIPR2 CNV的鼠标模型。 BAC的条件设计允许关闭所需的转换 由CRE重组酶控制的时空模式，从而支持解剖造成的细胞 人群。遗传过度激活的VIPR2信号引起早期的小胶质细胞修剪防御和 表现出强大的社会缺陷。因此，我们提出了过度激活的VIP/VIPR2的中心假设 T细胞中的信号传导引起异常的免疫转变，以破坏社会脑发育和/或社会 行为。该假设将在以下具体目的中进行检查：AIM 1将检查潜力 VIPR2 CNV在T细胞中的致病作用引起全身免疫失衡，破坏产后早期的大脑 发展。这个目标代表了第一个使用设计器受体采用化学发生方法的目标 由设计师药物（Dreadd）与CREB-荧光素酶报告基因转基因一起激活 远程控制T细胞类型特异性GαSGPCR/PKA信号传导，以确定VIPR2驱动的TH2是否驱动 优先区分足以引起社会缺陷和大脑发育不足。我们提出的 与病因相关的动物模型中的遗传询问将通过提供的方式来改变该领域的范式 第一次明确的因果证据表明，功能失调的免疫力足以破坏 大脑发展和/或表现社会行为定义。鉴于没有修改疾病的疗法 对于自闭症和精神分裂症，我们的结果将产生重要的积极影响，因为它们奠定了基础 针对T细胞免疫的治疗量量量量量的量身定制（例如，小分子VIPR2拮抗剂） 解决社会症状的解决，这是高度创新的，具有巨大的翻译价值。